Compounds

ABSTRACT

Compounds of formula (I) wherein R is hydroxy, hydrogen, alkenyl, alkynyl or aryl, and R1 is aryl or heteroaryl, are useful in the treatment and prophylaxis of conditions mediated by CD23 or TNF.

This application is a §371 application of PCT/EP98/01766 filed on Mar.16, 1998.

This invention relates to novel inhibitors of the formation of solublehuman CD23 and their use in the treatment of conditions associated withexcess production of soluble CD23 (s-CD23) such as autoimmune diseaseand allergy.

CD23 (the low affinity IgE receptor FceRII, Blast 2), is a 45 kDa typeII integral protein expressed on the surface of a variety of maturecells, including B and T lymphocytes, macrophages, natural killer cells,Langerhans cells, monocytes and platelets (Delespesse et al, AdvImmunol, 49 [1991] 149-191). There is also a CD23-like molecule oneosinophils (Grangette et al, J Immunol, 143 [1989] 3580-3588). CD23 hasbeen implicated in the regulation of the immune response (Delespesse etal, Immunol Rev, 125 [1992] 77-97). Human CD23 exists as twodifferentially regulated isoforms, a and b, which differ only in theamino acids at the intracellular N-terminus (Yokota et al, Cell, 55[1988] 611-618). In man the constitutive a isoform is found only onB-lymphocytes, whereas type b, inducible by IL4, is found on all cellscapable of expressing CD23.

Intact, cell bound CD23 (i-CD23) is known to undergo cleavage from thecell surface leading to the formation of a number of well-definedsoluble fragments (s-CD23), which are produced as a result of a complexsequence of proteolytic events, the mechanism of which is still poorlyunderstood (Bourget et al J Biol Chem, 269 [1994] 6927-6930). Althoughnot yet proven, it is postulated that the major soluble fragments (Mr37, 33, 29 and 25 kDa) of these proteolytic events, all of which retainthe C-terminal lectin domain common to i-CD23, occur sequentially viainitial formation of the 37 kDa fragment (Letellier et al, J Exp Med,172 [1990] 693-700). An alternative intracellular cleavage pathway leadsto a stable 16 kDa fragment differing in the C-terminal domain fromi-CD23 (Grenier-Brosette et al, Eur J Immunol, 22 [1992] 1573-1577).

Several activities have been ascribed to membrane bound i-CD23 inhumans, all of which have been shown to play a role in IgE regulation.Particular activities include: a) antigen presentation, b) IgE mediatedeosinophil cytotoxicity, c) B cell homing to germinal centres of lymphnodes and spleen, and d) downregulation of IgE synthesis (Delespesse etal, Adv Immunol, 49, [1991] 149-191). The three higher molecular weightsoluble CD23 fragments (Mr 37, 33 and 29 kDa) have multifunctionalcytokine properties which appear to play a major role in IgE production.Thus, the excessive formation of s-CD23 has been implicated in theoverproduction of IgE, the hallmark of allergic diseases such asextrinsic asthma, rhinitis, allergic conjuctivitis, eczema, atopicdermatitis and anaphylaxis (Sutton and Gould, Nature, 366, [1993]421-428).

Other biological activities attributed to s-CD23 include the stimulationof B cell growth and the induction of the release of mediators frommonocytes. Thus, elevated levels of s-CD23 have been observed in theserum of patients having B-chronic lymphocytic leukaemia (Sarfati et al,Blood, 71 [1988] 94-98) and in the synovial fluids of patients withrheumatoid arthritis (Chomarat et al, Arthritis and Rheumatism, 36[1993] 234-242). That there is a role for CD23 in inflammation issuggested by a number of sources. First, sCD23 has been reported to bindto extracellular receptors which when activated are involved incell-mediated events of inflammation. Thus, sCD23 is reported todirectly activate monocyte TNF, IL-1, and IL-6 release (Armant et al,vol 180, J.Exp. Med., 1005-1011 (1994)). CD23 has been reported tointeract with the B2-integrin adhesion molecules, CD11b and CD11c onmonocyte/macrophage (S. Lecoanet-Henchoz et al, Immunity, vol 3; 119-125(1995)) which trigger NO2⁻, hydrogen peroxide and cytokine (IL-1, IL-6,and TNF) release. Finally, IL-4 or IFN induce the expression of CD23 andits release as sCD23 by human monocytes. Ligation of the membrane boundCD23 receptor with IgE/anti-IgE immune complexes or anti CD23 mAbactivates cAMP and IL-6 production and thromboxane B2 formation,demonstrating a receptor-mediated role of CD23 in inflammation.

Because of these various properties of CD23, compounds which inhibit theformation of s-CD23 should have twofold actions of a) enhancing negativefeedback inhibition of IgE synthesis by maintaining levels of i-CD23 onthe surface of B cells, and b) inhibiting the immunostimulatory cytokineactivities of higher molecular weight soluble fragments (Mr 37, 33 and29 kDa) of s-CD23. In addition, inhibition of CD23 cleavage shouldmitigate sCD23-induced monocyte activation and mediator formation,thereby reducing the inflammatory response.

TNFα is a pro-inflammatory cytokine which is released from stimulatedcells by specific cleavage of a 76-amino acid signal sequence in theinactive precursor to generate the mature form. The cleavage of TNFα hasbeen reported to be carried out by a metalloprotease (Gearing, A. J. H.et al, (1994) Nature 370, 555-557; McGeehan, G. M. et al, (1994) Nature370, 558-561; Mohler, K. M. et al, (1994) Nature 370, 218-220).Compounds reported to inhibit the cleavage of TNFα by the TNF processingenzyme can be broadly described as matrix metalloprotease inhibitors,particularly of the hydroxamic acid class.

TNFα is induced in a variety of cell types in response to bacteria,endotoxin, various viruses and parasites, so that one physiologicalfunction ascribed to TNFα is a contribution to the inflammatory responseto acute infection by bacteria, parasites, etc (Dinarelo, Calif. (1992)Immunol. 4, 133-145). Overproduction of TNFα has been implicated indisease states such as rheumatoid arthritis, septic shock, Crohn'sdisease and cachexia (Dinarello, 1992). Inhibition of processing of TNFαto the mature, active form would therefore be beneficial in thetreatment of these inflammatory disorders. TNFα may also contribute tothe destruction of tissue in autoimmune disease although it is not aninitiating factor in these diseases. Confirming the importance of TNFαin rheumatoid arthritis, TNFα antibodies have been shown to reduce theseverity of disease in short term studies in rheumatoid arhritis models(Elliott, M. J., et al (1993) Arthrit. Rheum. 12, 1681-1690; Elliott etal (1994) Lancet 344, 1125-1127).

According to the present invention, there is provided a compound offormula (I):

wherein R is hydroxy, hydrogen, alkenyl, alkynyl or aryl, and R1 is arylor heteroaryl.

Alkyl, alkenyl and alkynyl groups referred to herein include straightand branched groups containing up to six carbon atoms and are optionallysubstituted by one or more groups selected from the group consisting ofaryl, heterocyclyl, (C₁₋₆)alkylthio, (C₂₋₆)alkenylthio,(C₂₋₆)alkynylthio, arylthio, heterocyclylthio, (C₁₋₆)alkoxy,aryl(C₁₋₆)alkoxy, aryl(C₁₋₆)alkylthio, amino, mono- ordi-(C₁₋₆)alkylamino, cycloalkyl, cycloalkenyl, carboxy and estersthereof, hydroxy, and halogen.

Cycloalkyl and cycloalkenyl groups referred to herein include groupshaving between three and eight ring carbon atoms and are optionallysubstituted as described hereinabove for alkyl, alkenyl and allynylgroups.

When used herein, the term “aryl” includes phenyl and naphthyl such as2-naphthyl. Suitably any aryl group, including phenyl and naphthyl, maybe optionally substituted by up to five, preferably up to threesubstituents. Suitable substituents include halogen, (C₁₋₆)alkyl,aryl(C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkoxy(C₁₋₆)alkyl, halo(C₁₋₆)alkylhydroxy, nitro, amino, mono- and di-N-(C₁₋₆)alkylamino, acylamino,acyloxy, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- anddi-N-(C₁₋₆)alkylcarbamoyl, (C₁₋₆)alkoxycarbonyl, aryloxycarbonyl,ureido, guanidino, sulphonylamino, aminosulphonyl, (C₁₋₆)alkylthio,(C₁₋₆)alkyl sulphinyl (C₁₋₆)alkylsulphonyl, heterocyclyl andheterocyclyl (C₁₋₆)alkyl. In addition, two adjacent ring carbon atomsmay be linked by a (C₃₋₅)alkylene chain, to form a carbocyclic ring.Thus, the term “aryl” includes single and fused rings, of which at leastone is aromatic, which rings may be unsubstituted or substituted by, forexample, up to three substituents as set out above. Each ring suitablyhas from 4 to 7, preferably 5 or 6, ring atoms.

When used herein the terms “heterocyclyl” and “heterocyclic” suitablyinclude, unless otherwise defined, aromatic and non-aromatic, single andfused, rings suitably containing up to four heteroatoms in each ring,each of which is selected from oxygen, nitrogen and sulphur, whichrings, may be unsubstituted or substituted by, for example, up to threesubstituents. Each ring suitably has from 4 to 7, preferably 5 or 6,ring atoms. A fused heterocyclic ring system may include carbocyclicrings and need include only one heterocyclic ring.

When used herein the term “heteroaryl” suitably includes anyheterocyclyl group which incorporates at least one aromatic ring(heterocyclic or carbocyclic).

Preferably a substituent for a heterocyclyl group is selected fromhalogen, (C₁₋₆)alkyl, aryl(C₁₋₆)alkyl, (C₁₋₆)alkoxy,(C₁₋₆)alkoxy(C₁₋₆)alkyl, halo(C₁₋₆)alkyl, hydroxy, amino, mono- anddi-N-(C₁₋₆)alkyl-amino, acylamino, carboxy salts, carboxy esters,carbamoyl, mono- and di-N-(C₁₋₆)alkylcarbonyl, aryloxycarbonyl,(C₁₋₆)alkoxycarbonyl(C₁₋₆)alkyl, aryl, oxy groups, ureido, guanidino,sulphonylamino, aminosulphonyl, (C₁₋₆)alkylthio, (C₁₋₆)alkylsulphinyl,(C₁₋₆)alkylsulphonyl, heterocyclyl and heterocyclyl(C₁₋₆)alkyl.

In a particular aspect of the invention, R is isopropyl; isobutyl, or4-(uffluoroacetamido)butyl, and/or R1 is a phenyl group, optionallysubstituted, for example by methoxy, such as 4-methoxyphenyl, or a fusedaromatic group such as 2-naphthyl, or 5-(2-pyridyl)thiophen-2-yl.

According to a further aspect, the present invention provides the use ofa compound of formula (I) for the production of a medicament for thetreatment or prophylaxis of disorders such as allergy, inflammatorydisorders, and autoimmune disease, in which the overproduction of s-CD23is implicated.

In a further aspect the invention provides a method for the treatment orprophylaxis of disorders such as allergy, inflammatory disorders, andautoimmune disease, in which the overproduction of s-CD23 is implicated,which method comprises the administration of a compound of formula (I),to a human or non-human mammal in need thereof.

The invention also provides a pharmaceutical composition for thetreatment or prophylaxis of disorders such as allergy, inflammatorydisorders, and autoimmune disease, in which the overproduction of s-CD23is implicated which comprises a compound of formula (I) and optionally apharmaceutically acceptable carrier therefor.

Particular inflammatory disorders include CNS disorders such asAlzheimers disease, multiple sclerosis, and multi-infarct dementia, aswell as the inflammation mediated sequelae of stroke and head trauma.

According to a further aspect, the present invention provides the use ofa compound of formula (I) for the production of a medicament for thetreatment or prophylaxis of conditions mediated by TNF, including, butnot limited to, inflammation, fever, cardiovascular effects,haemorrhage, coagulation and acute phase response, cachexia andanorexia, acute infections, shock states, graft versus host reactionsand autoimmune disease.

In a further aspect the invention provides a method for the treatment orprophylaxis of conditions mediated by TNF, which method comprises theadministration of a compound of formula (I), to a human or non-humanmammal in need thereof.

The invention also provides a pharmaceutical composition for thetreatment or prophylaxis of conditions mediated by TNF, which comprisesa compound of formula (I) and optionally a pharmaceutically acceptablecarrier therefor.

The present inventors have surprisingly found that the compounds of theinvention are potent and selective inhibitors of both CD23 processingand TNF processing, whilst having little or no activity as inhibitors ofmatrix metalloproteases. A further aspect of the invention thus providesthe use of a TNF processing inhibitor for the production of a medicamentfor the treatment or prophylaxis of conditions mediated by sCD23,characterised in that the TNF processing inhibitor is not an inhibitorof matrix metalloprotease.

It is to be understood that the pharmaceutically acceptable salts,solvates and other pharmaceutically acceptable derivatives of thecompound of formula (I) are also included in the present invention.

Salts of compounds of formula (I) include for example acid additionsalts derived from inorganic or organic acids, such as hydrochlorides,hydrobromides, hydroiodides, p-toluenesulphonates, phosphates,sulphates, acetates, trifluoroacetates, propionates, citrates, maleates,fumarates, malonates, succinates, lactates, oxalates, tartrates andbenzoates.

Salts may also be formed with bases. Such salts include salts derivedfrom inorganic or organic bases, for example alkali metal salts such assodium or potassium salts, and organic amine salts such as morpholine,piperidine, dimethylamine or diethylamine salts.

The compounds of the invention may be prepared by use of any appropriateconventional method, for example by analogy with the methods disclosedin patent publication EP-A-0 606 046.

Accordingly, a further aspect of the invention provides a process forpreparing a compound of formula (I) as defined hereinabove, whichprocess comprises:

(a) deprotecting a compound of formula (II):

 wherein R and R1 are as defined hereinabove, and X is a protectinggroup such as benzyl or trimethylsilyl or

(b) reacting a compound of formula (III):

 wherein R and R1 are as defined hereinabove, with hydroxylamine or asalt thereof, or

(c) converting a compound of formula (I) to a different compound offormula (I) as defined hereinabove.

Compounds of formula (II) are novel and form a further aspect of theinvention.

Compounds of formula (II) can be prepared from compounds of formula(III) by reaction with a protected hydroxylamine. Compounds of formula(III) can be prepared by hydrolysis of a compound of formula (IV):

wherein R and R1 are as defined hereinabove, and Y is a protecting groupsuch as t-butyl.

Suitable protecting groups for a hydroxarnic acid are well known in theart and include benzyl, trimethylsilyl, t-butyl andt-butyldimethylsilyl.

Suitable protecting groups for a carboxylic acid are well known in theart and include t-butyl , benzyl and methyl.

Compounds of formula (IV) can be prepared by reacting a compound offormula (V):

wherein R and Y are as defined hereinabove, with a compound of formulaR¹SO₃H, wherein R1 is as defined hereinabove, or an activated derivativethereof, such as an arylsulfonyl chloride.

The starting materials and other reagents are available commercially orcan be synthesised by well-known and conventional methods.

The isomers, including stereoisomers, of the compounds of the presentinvention may be prepared as mixtures of such isomers or as individualisomers. The individual isomers may be prepared by any appropriatemethod, for example individual stereoisomers may be prepared bystereospecific chemical synthesis starting from chiral substrates or byseparating mixtures of diastereoisomers using known methods. In apreferred aspect, the invention provides compounds of formula (IA):

It is preferred that the compounds are isolated in substantially pureform.

As stated herein an inhibitor of the formation of soluble human CD23 hasuseful medical properties. Preferably the active compounds areadministered as pharmaceutically acceptable compositions.

The compositions are preferably adapted for oral administration.However, they may be adapted for other modes of administration, forexample in the form of a spray, aerosol or other conventional method forinhalation, for treating respiratory tract disorders; or parenteraladministration for patients suffering from heart failure. Otheralternative modes of administration include sublingual or transdermaladministration.

The compositions may be in the form of tablets, capsules, powders,granules, lozenges, suppositories, reconstitutable powders, or liquidpreparations, such as oral or sterile parenteral solutions orsuspensions.

In order to obtain consistency of administration it is preferred that acomposition of the invention is in the form of a unit dose.

Unit dose presentation forms for oral administration may be tablets andcapsules and may contain conventional excipients such as binding agents,for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinylpyrrolidone, sodium starch glycollate or microcrystallinecellulose; or pharmaceutically acceptable wetting agents such as sodiumlauryl sulphate.

The solid oral compositions may be prepared by conventional methods ofblending, filling or tabletting. Repeated blending operations may beused to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are of courseconventional in the art. The tablets may be coated according to methodswell known in normal pharmaceutical practice, in particular with anenteric coating.

Oral liquid preparations may be in the form of, for example, emulsions,syrups, or elixirs, or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel, hydrogenated edible fats; emulsifying agents, for examplelecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (whichmay include edible oils), for example almond oil, fractionated coconutoil, oily esters such as esters of glycerine, propylene glycol, or ethylalcohol; preservatives, for example methyl or propyl p-hydroxybenzoateor sorbic acid; and if desired conventional flavouring or colouringagents.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, and, depending on theconcentration used, can be either suspended or dissolved in the vehicle.In preparing solutions the compound can be dissolved in water forinjection and filter sterilized before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, a preservative and buffering agents can be dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilized by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

Compositions of this invention may also suitably be presented foradministration to the respiratory tract as a snuff or an aerosol orsolution for a nebulizer, or as a microfine powder for insufflation,alone or in combination with an inert carrier such as lactose. In such acase the particles of active compound suitably have diameters of lessthan 50 microns, preferably less than 10 microns for example diametersin the range of 1-50 microns, 1-10 microns or 1-5 microns. Whereappropriate, small amounts of other anti-asthmatics and bronchodilators,for example sympathomimetic amines such as isoprenaline, isoetharine,salbutamol, phenylephrine and ephedrine; xanthine derivatives such astheophylline and aminophylline and corticosteroids such as prednisoloneand adrenal stimulants such as ACTH may be included.

The compositions may contain from 0.1% to 99% by weight, preferably from10-60% by weight, of the active material, depending upon the method ofadministration. A preferred range for inhaled administration is 10-99%,especially 60-99%, for example 90, 95 or 99%.

Microfine powder formulations may suitably be administered in an aerosolas a metered dose or by means of a suitable breath-activated device.

Suitable metered dose aerosol formulations comprise conventionalpropellants, cosolvents, such as ethanol, surfactants such as oleylalcohol, lubricants such as oleyl alcohol, desiccants such as calciumsulphate and density modifiers such as sodium chloride.

Suitable solutions for a nebulizer are isotonic sterilised solutions,optionally buffered, at for example between pH 4-7, containing up to 20mg/ml of compound but more generally 0.1 to 10 mg/ml, for use withstandard nebulisation equipment.

An effective amount will depend on the relative efficacy of thecompounds of the present invention, the severity of the disorder beingtreated and the weight of the sufferer. Suitably, a unit dose form of acomposition of the invention may contain from 0.1 to 1000 mg of acompound of the invention (0.001 to 10 mg via inhalation) and moreusually from 1 to 500 mg, for example 1 to 25 or 5 to 500 mg. Suchcompositions may be administered from 1 to 6 times a day, more usuallyfrom 2 to 4 times a day, in a manner such that the daily dose is from 1mg to 1 g for a 70 kg human adult and more particularly from 5 to 500mg. That is in the range of about 1.4×10⁻² mg/kg/day to 14 mg/kg/day andmore particularly in the range of about 7×10⁻² mg/kg/day to 7 mg/kg/day.

The following examples illustrate the invention but do not limit it inany way.

EXAMPLE 12-(R)N-Hydroxy-[(4-Metioxybenzene)sulfonyl]amino-3-methylbutyramide

a) 2-(R)-N-[(4-methoxybenzene)sulfonyl]valine

To a solution on D-valie (10 g, 85.4 mmol) in 1,4-dioxan (200 ml) andwater (100 ml) at 0° C. was added triethylamine (59 ml, 427 mmol)followed by 4-methoxybenzene sulfonylchioride (21 g, 102 mmol). Thesolution was allowed to warm to ambient temperature and stiffed for 2days. The organic solvent was removed at reduced pressure and theresidue made alkaline with sodium bicarbonate. This solution wasextracted with ethyl acetate, then acidified using 2N HCl and extractedwith ethyl acetate (×2). These extracts were dried and the solventremoved under reduced pressure to give the title compound (22 g, 90%) asa white solid.

1H nmr (d₆-DMSO) 0.74 (6H, d, J=6.9 Hz), 1.68-1.99 (1H, m), 3.20-3.28(1H, m), 3.82 (3H, s), 7.04 (2H, d, J=9 Hz), 7.68 (2H, d, J=9 Hz),7.66-7.73 (1H, br), 10.7 (1H,br.)

b) 2-(R)-N-Hydroxy-[(4Methoxybenzene)sulfonyl]amino-3-methylbutyramide

To a solution of 2-(R)-N-[(4-methoxybenzene)sulfonyl]valine (1 g, 3.5mmol) in DMF (72 ml) was added 1-hydroxy-7-azabenzotriazole (HOAt, 629mg, 4.5 mmol), 1-(3-dimethylaminopropyl)3-ethylcarbodiimidehydrochloride (DEC, 879 mg, 4.5 mmol), hydroxylamine hydrochloride (278mg, 3.8 mmol) and N-methylmorpholine (0.5 ml, 3.8 mmol) and the solutionstirred for 18 h. The solvent was removed under reduced pressure and theresidue dissolved in ethyl acetate then washed with citric acid (10%solution), sodium bicarbonate (satd) and brine. The solution was driedand concentrated under reduced pressure to give a yellow foam which wastriturated with diethyl ether to yield a white solid (0.5 g, 48%)

MH⁺ 303, MNa⁺ 325; 1H nmr (d₆-DMSO) 0.73 (6H, d, J=6.9 Hz), 1.68-1.99(1H, m), 3.21-3.28 (1H, m), 3.82 (3H, s), 7.04 (2H, d, J=8.8 Hz), 7.(2H, d, J=8.8 Hz), 7.66-7.73 (1H, br), 8.77 (1H, s), 10.47 (1H, s).

EXAMPLE 22-(R)-N-Hydroxy-[(2-naphthyl)sulfonyl]andno-3-methiylbutyraniide

This was prepared from 2-(R)-N-[(4-methoxybenzene)sulfonyl]valine and2-naphthylsulfonylchloride by the procedure of example 1b (45%) as acream solid.

MNH₄ ⁺ 340; 1H nmr (d₆-DMSO) 0.71-0.76 (6H,m), 1.74-1.81 (1H, m),3.27-3.36 (1H, m), 7.63-7.68 (2H, m), 7.80 (1H, d, J=8.5 Hz), 8.01-8.12(4H, m), 8.37 (1H, s), 8.75 (1H, s), 10.51 (1H, s).

EXAMPLE 3

a) N((5-(2-pyridyl)thiophen-2-ylsulfonyl)-(R)-leucine

The title compound was prepared as in Example 1.

NMR: (DMSO-d6) δ 0.80 (3H, d, J=6.5 Hz), 0.87 (3H, d, J=6.5 Hz), 1.46(2H, m), 1.66 (1H, septet, J=6.3 Hz), 3.79 (1H, m), 7.41 (1H, m), 7.59(1H, d, J=4 Hz), 7.84 (1H, d, J=4 Hz), 7.94 (1H, m), 8.07 (1H, d, J=8Hz), 8.45 (1H, v. br. s), 8.62 (1H, d, J=4.2 Hz); MS: (M+H)=355.

b) N-hydroxy-Nα((5-(2-pyridylthiophen-2-yisulfonyl)-(R)-leucinamide

The title compound was prepared as in Example 1

NMR: (DMSO-d6) δ 0.70 (1H, d, J=6.4 Hz), 0.78 (1H, d, J=6.4 Hz), 1.33(2H, m), 1.47 (1H, septet, J=6.4 Hz), 3.65 (1H, m), 7.38 (1H, m), 7.54(1H, d, J=4 Hz), 7.80 (1H, d, J=4 Hz), 7.90 (1H, m), 8.02 (1H, d, J=7.9Hz), 8.30 (1H, br., d), 8.59 (1H, d, J=4.2 Hz), 8.87 (1H, s), 10.72 (1H,s); MS: (M+H)=370.

EXAMPLE 4

a)Nε-tertbutoxycarbonyl-Nα(5-(2-pyridyl)thiophen-2-ylsulfonyl)-(R)-lysine

The title compound was prepared as in Example 1

NMR: (DMSO-d6) δ 1.22-1.42 (4H, br., m), 1.41 (9H, s), 1.50-1.75 (2H,br., m), 2.88 (2H, br. q, J˜6 Hz), 3.79 (1H, m), 6.76 (1H, br., t), 7.44(1H, m), 7.61 (1H, d, J=4 Hz), 7.86 (1H, d, J=4 Hz), 7.96 (1H, m), 8.08(1H, d, J=8 Hz), 8.64 (1H, d J=4.2 Hz); MS: (M+H)=470.

b)Nε-tertbutoxycarbonyl-N-hydroxy-Nα-(5-(2-pyridyl)thiophen-2-ylsulfonyl)(R)-lysinamide

The tide compound was prepared as in Example 1

NMR: (DMSO-d6) δ 1.0-1.36 (4H, br., m), 1.36-1.56 (2H, br., m), 1.36(9H, s). 2.79 (2H, br. q, J˜6 Hz), 3.67 (1H, br. m), 6.70 (1H, br., t),7.40 (1H, m), 7.56 (1H, d, J=4 Hz), 7.82 (1H, d, J=4 Hz), 7.93 (1H, m),8.04 (1H, d, J=8 Hz), 8.33 (1H, d, J˜7 Hz, SO₂NH), 8.60 (1H, d, J=4.2Hz), 8.89 (1H, s), 10.64 (1H, s); MS: (M+H)=485.

c) N-hydroxy-Nα(5-(2-pyridyl)thiophen-2-ylsulfonyl)-(R)-lysinamidetrifluoroacetate salt

The title compound was prepared by treatment ofNε-tertbutoxycarbonyl-N-hydroxy-Nα-(5-(2-pyridyl)thiophen-2-yisulfonyl)-(R)-lysinamidewith trfluoracetic acid: dichioromethane (1:1) until all startingmaterial had disappeared (tlc), then removal of volatiles.

NMR: (DMSO-d6) δ 1.1-1.65 (6H, br., m), 2.75 (2H, m), 3.71 (1H, br., q),7.25 (1H, m), 7.45 (1H, m), 7.61 (1H, d, J=4 Hz), 7.68 (˜2H, br., s),7.88 (1H, d, J=4 Hz), 7.98 (1H, m), 8.11 (1H, d, J=8 Hz), 8.43 (1H, d,J=8.5 Hz), 8.65 (1H, d, J=4.2 Hz), 10.75 (1H, s); MS: (M+H)=385.

What is claimed is:
 1. A compound of formula (I):

wherein R is hydroxy, hydrogen, isopropyl; isobutyl, or4-(trifluoroacetamido)butyl, alkenyl, alkynyl or aryl, and R1 is2-naphthyl, 4-methoxyphenyl or 5-(2-pyridyl)thiophen-2-yl.
 2. A compoundselected from the group consisting of2-(R)-N-Hydroxy-[(4-Methoxybenzene)sulfonyl]amino-3-methylbutyramide2-(R)-N-Hydroxy-[(2-naphthyl)sulfonyl]amino-3-methylbutyramideN-hydroxy-Nα((5-(2-pyridyl)thiophen-2-ylsulfonyl)-(R)-leucinamideN-hydroxy-Nα(5-(2-pyridyl)thiophen-2-ylsulfonyl)-(R)-lysinamidetrifluoroacetate salt.
 3. A compound of formula (II):

wherein R and R1 are as defined in claim 1, and X is a protecting group.4. A pharmaceutical composition for the treatment or prophylaxis ofdisorders in which the overproduction of s-CD23 is implicated whichcomprises a compound according to claim 1 and optionally apharmaceutically acceptable carrier therefor.
 5. A pharmaceuticalcomposition for the treatment or prophylaxis of conditions mediated byTNF, which comprises a compound according to claim 1 and optionally apharmaceutically acceptable carrier therefor.
 6. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticalacceptable carrier thereof for the treatment or prophylaxis ofconditions mediated by sCD23, which comprises a TNF processinginhibitor, characterised in that the TNF processing inhibitor is not aninhibitor of matrix metalloprotease.
 7. A method for the treatment orprophylaxis of disorders in which the overproduction of s-CD23 isimplicated, which method comprises the administration of a compoundaccording to claim 1 to a human or non-human mammal in need thereof. 8.A method for the treatment or prophylaxis of conditions mediated by TNF,which method comprises the administration of a compound according toclaim 1 to a human or non-human mammal in need thereof.
 9. A process forpreparing a compound according to claim 1 which process comprises: (a)deprotecting a compound of formula (II):

 wherein R is hydroxy, hydrogen, isopropyl, isobutyl, or4-(trifluoroacetamido)butyl, alkenyl, alkynyl, or aryl and R1 is2-naphthyl, 4-methoxyphenyl or 5-(2-pyridyl)thiophen-2-yl in claim 1,and X is a protecting group, or (b) reacting a compound of formula(III):

 wherein R is hydroxy, hydrogen, isopropyl, isobutyl, or4-(trifluoroacetamido)butyl, alkenyl, alkynyl, or aryl and R1 is2-naphthyl, 4-methoxyphenyl or 5-(2-pyridyl)thiophen-2-yl in claim 1,with hydroxylamine or a salt thereof.